The present invention relates to devices and methods for administering ophthalmic solutions to the eye. In particular, the present invention relates to devices and methods for administering ophthalmic solutions to the portion of the cornea called the stroma. The following patents and patent applications disclose subject matter related to the present invention and the contents thereof are incorporated herein by reference in their entirety.
This application is related to:                U.S. Pat. Nos. 6,537,545, 6,946,440 and 7,402,562;        U.S. Patent Application Publication No. 2009/0105127;        U.S. Provisional Patent Application Nos. 61/241,607, filed Sep. 11, 2009, 61/266,705, filed Dec. 4, 2009, and 61/308,589, filed Feb. 26, 2010;        PCT International Publication Nos. WO 2009/114513, WO 2009/120549, WO 2009/120550; and        PCT Application No. PCT/US2007/008049, filed Apr. 3, 2007, and PCT Application No. PCT/US2010/25036, filed Feb. 23, 2010.        
The cornea is the first and most powerful refracting surface of the optical system of the eye. The human cornea is a highly specialized tissue combining optical transparency with mechanical strength. It is made up of five layers, the outermost of which is the epithelium. The epithelium is only four to five cells thick, and renews itself continuously. Underneath the epithelium, the second layer is the acellular Bowman's membrane. It is composed of collagen fibrils and normally transparent. Below Bowman's membrane, the third layer, and largest part of the cornea, is the stroma. The stroma makes up approximately 90% of the cornea's thickness, and is about 500 microns (μm) thick.
The stroma comprises a well organized matrix architecture composed of approximately 200 parallel sheets of narrow-diameter collagen fibrils arranged orthogonal to neighboring fibril sheets. Corneal fibrils are primarily composed of Type I collagen co-assembled with Type V collagen. Small leucine-rich repeat proteoglycans (SLRPs), such as decorin, are critical for maintaining corneal transparency and corneal strength. The stroma is mostly water (78%) and collagen (16%), although other proteoglycans and glycoproteins are also present.
When the cornea is misshapen or injured, vision impairment can result. In the case of a misshapen cornea, eyeglasses and contact lenses have traditionally been used to correct refractive errors, but refractive surgical techniques are now also routinely used. There are currently several different techniques in use.
One such vision correction technique is radial keratotomy (RK). In radial keratotomy (RK), several deep incisions are made in a radial pattern around the cornea, so that the central portion of the cornea flattens. Although this can correct the patient's vision, it also weakens the cornea, which may continue to change shape following the surgery.
Photorefractive keratectomy (PRK) is another vision correction technique. It uses an excimer laser to sculpt the surface of the cornea. In this procedure, the epithelial basement membrane is removed, and Bowman's membrane and the anterior stroma are photoablated. However, some patients with initially good results may experience, in the months following the procedure, a change in their refraction caused by distortion of the cornea and/or other anomalies. Collectively, these changes in refraction may be referred to as “regression.” In addition, corneal haze can also occur following PRK, and the greater the correction attempted, the greater the incidence and severity of the haze.
Laser in situ keratomileusis (LASIK) is yet another alternative. In this technique, an epithelial-stromal flap is cut with a microkeratome (or a laser). The flap is flipped back on its hinge, and the underlying stroma is ablated with a laser. The flap is then reseated. There is a risk that the flap created will later dislodge, however. In addition, the CRS-USA LASIK Study noted that overall, 5.8% of LASIK patients experienced complications at the three-month follow up period that did not occur during the procedure itself. These complications included corneal edema (0.6%), corneal scarring (0.1%), persistent epithelial defect (0.5%), significant glare (0.2%), persistent discomfort or pain (0.5%), interface epithelium (0.6%), cap thinning (0.1%) and interface debris (3.2%).
Most patients will have stable results after LASIK. That is, the one month to three month results will usually be permanent for most patients. However, some patients with initially good results may experience a change in their refraction (i.e., regression) over the first 3 to 6 months (and possibly longer). LASIK can result in haze as well, although less frequently than with PRK, presumably because LASIK preserves the central corneal epithelium.
The chance of having regression following LASIK is related to the initial amount of refractive error. Patients with higher degrees of myopia (−8.00 to −14.00) are more likely to experience regression. For example, a −10.00 myope may initially be 20/20 after LASIK at the 2 week follow-up visit. However, over the course of the next 3 months, the refractive error may shift (regress) from −0.25 to −1.50 (or even more). This could reduce the patient's visual acuity without glasses to less than 20/40, a point at which the patient would consider having an enhancement.
All surgical procedures involve varying degrees of traumatic injury to the eye and a subsequent wound healing process. Netto et al., Cornea, Vol. 24, pp. 509-22 (2005). Regression occurs often as a result of a reduction of biomechanical structural integrity caused by the procedure. For example, one type of postoperative regression is keratectasia. Keratectasia is an abnormal bulging of the cornea. In keratectasia, the posterior stroma thins, possibly due to interruption of the crosslinks of collagen fibers and/or altered proteoglycans composition, reducing the stiffness of the cornea and permitting it to shift forward. Dupps, W. J., J. Refract. Surg., Vol. 21, pp. 186-90 (2005). The forward shift in the cornea causes a regression in the refractive correction obtained by the surgical procedure.
In the past several years there has been increasing concern regarding the occurrence of keratectasia following LASIK. In LASIK, the cornea is structurally weakened by the laser ablation of the central stroma and by creation of the flap. While the exact mechanism of this phenomenon is not completely known, keratectasia can have profound negative effects on the refractive properties of the cornea. In some cases, the cornea thins and the resultant irregular astigmatism cannot be corrected, potentially requiring PRK to restore vision. The incidence of keratectasia following LASIK is estimated to be 0.66% (660 per 100,000 eyes) in eyes having greater than −8 diopters of myopia preoperatively. Pallikaris et al., J. Cataract Refract. Surg., Vol. 27, pp. 1796-1802 (2001). Although at present keratectasia is a rare complication of refractive surgery, the number of refractive surgical procedures performed each year continues to increase and, therefore, even this rare condition will impact many individuals. T. Seiler, J. Cataract Refract. Surg., Vol. 25, pp. 1307-08 (1999).
In addition to corneal weakening resulting from surgical procedures, other conditions involve reduced structural integrity of the cornea. For example, keratoconus is a condition in which the rigidity of the cornea is decreased. Its frequency is estimated at 4-230 per 100,000. Clinically, one of the earliest signs of keratoconus is an increase in the corneal curvature, which presents as irregular astigmatism. The increase in curvature is thought to be due to stretching of the stromal layers. In advanced stages of keratoconus, a visible cone-shaped protrusion forms which is measurably thinner than surrounding areas of the cornea.
Keratoconus may involve a general weakening of the strength of the cornea, which eventually results in lesions in those areas of the cornea that are inherently less able to withstand the shear forces present within the cornea. Smolek et al., Invest. Ophthalmol. Vis. Sci. Vol. 38, pp. 1289-90 (1997). Andreassen et al., Exp. Eye Res., Vol. 31, pp. 435-41 (1980), compared the biomechanical properties of keratoconus and normal corneas and found a 50% decrease in the stress necessary for a defined strain in the keratoconus corneas.
The alterations in the strength of the cornea in keratoconus appear to involve both the collagen fibrils and their surrounding proteoglycans. For example, Daxer et al., Invest. Ophthalmol. & Vis. Sci., Vol. 38, pp. 121-29 (1997), observed that in normal cornea, the collagen fibrils were oriented along horizontal and vertical directions that correspond to the insertion points of the four musculi recti oculi. In keratoconus corneas, however, that orientation of collagen fibrils was lost within the diseased areas. In addition, Fullwood et al., Biochem. Soc. Transactions, Vol. 18, pp. 961-62 (1990), found that there is an abnormal arrangement of proteoglycans in the keratoconus cornea, leading them to suggest that the stresses within the stroma may cause slipping between adjacent collagen fibrils. The slippage may be associated with loss of cohesive forces and mechanical failure in affected regions. This may be related to abnormal insertion into Bowman's structure or to abnormalities in interactions between collagen fibrils and a number of stabilizing molecules such as Type VI collagen or decorin. Many of the clinical features of keratoconus can be explained by loss of biomechanical properties potentially resulting from interlamellar and interfibrillar slippage of collagen within the stroma and increased proteolytic degradation of collagen fibrils, or entire lamellae.
Because both keratoconus and postoperative keratectasia involve reduced corneal rigidity, relief from each condition could be provided by methods of increasing the rigidity of the cornea. For example, methods that increase the rigidity of the cornea can be used to treat postoperative keratectasia. The treatment can be administered to a patient who plans to undergo a refractive surgical procedure as a prophylactic therapy. In other cases, the treatment can be administered during the surgical procedure itself. In still other situations, the treatment may not be initiated until after the refractive surgical procedure. Of course, various combinations of treatment before, during, and after the surgery are also possible.
It has also been suggested that a therapeutic increase in the stiffness of the cornea could delay or compensate for the softening of the cornea that occurs in keratoconus. Spoerl et al., Exp. Eye Res., Vol. 66, pp. 97-103 (1998). While acknowledging that the basis for the differences in elasticity between normal and keratoconus corneas is unknown, those authors suggest that a reduction in collagen crosslinks and a reduction in the molecular bonds between neighboring stromal proteoglycans could play a role.
There are several treatments for increasing corneal rigidity and compensating for corneal softness. Some of these treatments suffer from drawbacks that include development of corneal haze and scarring, as well as the risk of endothelial cell damage. While some of these drawbacks are associated with the particular agents used, some of these drawbacks are associated with the techniques used to administer the agents. In addition, other such treatments, while practiced with some degree of success, could benefit from enhanced delivery of the agents to the cornea. The need exists, therefore, for system that provides improved delivery of agents to the cornea.
Riboflavin has been shown to reduce the progression of keratectasia in patients with keratoconus. Aldehydes have also been used to crosslink collagen fibers and, thereby improve the structural integrity of the cornea. For example, U.S. Pat. No. 6,537,545 describes the application of various aldehydes to a cornea in combination with a reshaping contact lens. The contact lens is used to induce the desired shape following either enzyme orthokeratology or refractive surgery, and the aldehyde is used to crosslink collagens and proteoglycans in the cornea. However, application of such agents can be problematic.
In addition, small leucine-rich repeat proteoglycans (SLRPs), such as decorin; fibril-associated collagens with interrupted triple helices (FACITs); or the enzyme transglutaminase, can be used to retard relaxation of corneal tissue back to the original curvature when used as an adjunct to an orthokerotological procedure. See U.S. Pat. No. 6,946,440. However, while there have been devices developed to contain solutions in an area on the surface of the cornea (see e.g., PCT International Publication No. WO 2009/120550), there has not been a delivery device that facilitates introduction of such agents directly into the subsurface portions of the stroma.
Although orthokeratology and surgical techniques such as LASIK seek to improve visual acuity using radically different approaches, the success of both orthokeratology and surgical techniques may be improved by increasing structural integrity of the cornea. Despite the fact that surgery disrupts the cornea and removes corneal tissue, methods of stabilizing collagen fibrils using proteins that crosslink the collagen fibrils, such as decorin or the enzyme transglutaminase, have been shown to improve the outcome following a surgical procedure to improve visual acuity. Those results also provide a basis for treating diseases of the cornea, such as keratectasia from other causes, such as keratoconus.
In addition to agents that increase the structural integrity of the cornea, there may be a desire to deliver other types of ophthalmic solutions, such as antibiotics and/or other agents, to the cornea.
For a number of different ophthalmic agents, it may be advantageous to deliver such agents directly to subsurface portions of the stroma. Although certain agents may be applied topically, in order to achieve penetration to a desired depth within the cornea, it is sometimes necessary to pretreat the cornea with agents that enhance penetration, such as agents that dissociate epithelial cell junctures. Further, even with penetration-enhancing agents, satisfactory penetration of agents to the desired depth of the cornea may not always be achievable.
The present disclosure is directed to improvements in delivery of ophthalmic solutions to the cornea.